Identification of novel therapeutic targets is critical to the advancement of cancer treatment. Currently, systemic cancer treatment regimes involve administering one or more highly toxic chemotherapeutics or hormonal therapies to the patient after the cancer has progressed to a point where the therapeutic benefits of chemotherapy/hormonal therapies outweigh its serious side effects. As a consequence of these side effects, standard chemotherapeutics are typically used only for short periods of time, often alternating chemotherapy with periods off treatment, so as not to overwhelm the patient with drug side effects. Accordingly, given the risk-benefit trade-off, side effects typically preclude starting chemotherapy when patients exhibit precancerous lesions, or continuing chemotherapy or hormonal therapy on a chronic basis after cancer has been eliminated in an attempt to prevent its re-occurrence.
Cancer and precancer research is replete with publications that describe various biochemical molecules that are over-expressed in neoplastic tissue, leading several groups to research whether specific over-expressed molecules are responsible for the disease, and whether, if such over-expression were inhibited, neoplasia could be alleviated. One group of such biochemical molecules that have been extensively studied as potential therapeutic targets for neoplasia treatments are the chemokines and their receptors. Chemokines constitute a family of small molecular weight cytokines that induce migration and activation of leukocytes and are necessary for the normal development of multiple tissues. These molecules are ligands for seven-transmembrane G protein linked receptors that induce a wide array of signaling cascades, productive of different cell type-specific responses. Thirteen different human chemokine receptors are known, including CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR1, CXCR2, CXCR3, CXCR4, and CCX-CKR2.
Binding of a chemokine to its receptor typically induces normal intracellular signaling responses such as a transient rise in cytosolic calcium concentration, followed by cellular biological responses such as chemotaxis. But over expression or aberrant activation of chemokines and their receptors, as detailed above, has been linked to cancer cell growth and spread. The chemokine receptor CXCR4, for example, is expressed in as many as 23 different tumor types, and is a particularly exciting new target for cancer therapy (1). Most models of CXCR4 function in cancer focus on its potential role as a mediator of motility, invasiveness and metastatic behavior (2). CXCR4 activation however, is also necessary for growth in intracranial models of primary brain tumors (3) as well as in models of primary breast cancer (4). The growth effects of CXCR4 activation are reminiscent of its role in normal hematopoiesis (5-7) or in cerebellar (8), hippocampal (9, 10) and retinal development (11). In all cases, CXCR4 activity is presumed to be ligand dependent. These studies suggested that cooperative signaling between CXCR4 and pathways that are activated by oncogenetic changes may be essential for tumor growth.
Despite advances in the field, the identification of new target molecules useful in the diagnosis and treatment of cancer and other diseases is a continuing need. In addition, methods for evaluating the role that target molecules play in cancer are also needed.